Abstract
Background
Recent studies have identified that low levels of some tumour suppressor microRNAs (miRNAs) in the blood contribute to tumour progression and poor outcomes in various cancers. However, no study has proved these miRNAs are associated with cancer immune mechanisms.
Methods
From a systematic review of the NCBI and miRNA databases, four tumour suppressor miRNA candidates were selected (miR-5193, miR-4443, miR-520h, miR-496) that putatively target programmed cell death ligand 1 (PD-L1).
Results
Test-scale and large-scale analyses revealed that plasma levels of miR-5193 were significantly lower in gastric cancer (GC) patients than in healthy volunteers (HVs). Low plasma levels of miR-5193 were associated with advanced pathological stages and were an independent prognostic factor. Overexpression of miR-5193 in GC cells suppressed PD-L1 on the surface of GC cells, even with IFN-γ stimulation. In the coculture model of GC cells and T cells stimulated by anti-CD3/anti-CD28 beads, overexpression of miR-5193 increased anti-tumour activity of T cells by suppressing PD-L1 expression. Subcutaneous injection of miR-5193 also significantly enhanced the tumour-killing activity and trafficking of T cells in mice.
Conclusions
Low blood levels of miR-5193 are associated with GC progression and poor outcomes and could be a target of nucleic acid immunotherapy in GC patients.
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Data availability
The datasets generated and/or analysed during the current study are not publicly available due to the personal information protection law in Japan but are available after the permission from the institutional review board and the corresponding author upon reasonable request.
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HK and SK designed, and SK and EO reviewed the research; HK, YT, TO, JK, HA and RI performed cell cultures, molecular biology and animal experiments; SK, TA, HS, HK, AS, TK, HF, SY, TI and EO provided clinical specimens and performed clinical data analyses. All authors read and approved the final manuscript.
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Ethics approval and consent to participate
All experimental methods were carried out in accordance with relevant guidelines and regulations, such as the Declaration of Helsinki. Written informed consent was obtained from all patients to use their tissue specimens and blood samples. This study was approved by the institutional review boards of Kyoto Prefectural University of Medicine (ERB-C-319-1). The animal protocol was approved by the Institutional Animal Care and Use Committee of Kyoto Prefectural University of Medicine, and all experiments were conducted strictly in accordance with the National Institute of Health Guide for Care and Use of Laboratory Animals.
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Kamiya, H., Komatsu, S., Takashima, Y. et al. Low blood level of tumour suppressor miR-5193 as a target of immunotherapy to PD-L1 in gastric cancer. Br J Cancer 130, 671–681 (2024). https://doi.org/10.1038/s41416-023-02532-3
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DOI: https://doi.org/10.1038/s41416-023-02532-3
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